sporadic alzheimer’s disease
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2022 ◽  
Vol 23 (1) ◽  
pp. 548
Author(s):  
Jelena Osmanovic Barilar ◽  
Ana Knezovic ◽  
Jan Homolak ◽  
Ana Babic Perhoc ◽  
Melita Salkovic-Petrisic

The incretin system is an emerging new field that might provide valuable contributions to the research of both the pathophysiology and therapeutic strategies in the treatment of diabetes, obesity, and neurodegenerative disorders. This study aimed to explore the roles of central glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) on cell metabolism and energy in the brain, as well as on the levels of these incretins, insulin, and glucose via inhibition of the central incretin receptors following intracerebroventricular administration of the respective antagonists in healthy rats and a streptozotocin-induced rat model of sporadic Alzheimer’s disease (sAD). Chemical ablation of the central GIP receptor (GIPR) or GLP-1 receptor (GLP-1R) in healthy and diseased animals indicated a region-dependent role of incretins in brain cell energy and metabolism and central incretin-dependent modulation of peripheral hormone secretion, markedly after GIPR inhibition, as well as a dysregulation of the GLP-1 system in experimental sAD.


2021 ◽  
pp. 1-15
Author(s):  
Sally Day ◽  
Stefanie Roberts ◽  
Nathalie H. Launder ◽  
Anita M.Y. Goh ◽  
Brian Draper ◽  
...  

Background: Understanding how the age of dementia symptom onset affects the longitudinal course of dementia can assist with prognosis and care planning. Objective: To synthesize evidence regarding the relationship of age of symptom onset with the longitudinal course of sporadic Alzheimer’s disease (AD), vascular dementia (VaD), and frontotemporal dementia (FTD). Methods: We searched Medline, CINAHL, Embase, PsycINFO, PubMed, and Scopus for longitudinal studies that examined the impact of sporadic AD, VaD, or FTD symptom onset age on measures of cognition, function, or behavioral symptoms. Studies that examined age at diagnosis only were excluded. Quantitative meta-analysis was conducted where studies reported sufficient data for pooling. Results: Thirty studies met all inclusion criteria (people with AD (n = 26), FTD (n = 4)) though no studies examined VaD. Earlier onset of AD was associated with more rapid annual cognitive decline (estimate = –0.07; 95% CI –0.14 to 0.00; p = 0.045). Most studies that stratified their sample reported that younger AD onset (usually <  65 years) was associated with more rapid cognitive decline. Other evidence was inconclusive. Conclusion: Younger people with AD appear to have a poorer prognosis in terms of faster cognitive decline than older people with AD. More research is required to determine the impact of symptom onset age in VaD and FTD, and on functional decline in all dementias.


2021 ◽  
Author(s):  
Victoria Cunha Alves ◽  
Joana Figueiro-Silva ◽  
Isidre Ferrer ◽  
Eva Carro

Abstract Modulation of brain olfactory (OR) and taste receptors (TASR) expression was recently reported in neurological diseases. We explored the possible expression and regulation of selected OR and TASR genes in human orbitofrontal cortex of sporadic Alzheimer’s disease (AD) and found that these are expressed and markedly downregulated at early stages. The expression pattern did not follow disease progression suggesting regulation through epigenetic mechanisms. We found an increase of global H3K9me3 levels and substantial enrichment of this repressive signature at ORs and TAS2Rs proximal promoter at early stages, ultimately lost at advanced stages. By mass spectrometry-based proteomic and further validation, we found that H3K9me3 interacts with MeCP2 at early stages and that this protein is increased in sporadic AD. Findings suggest MeCP2 might be implicated in OR and TAS2R genes expression regulation through interaction with H3K9me3, and as an early event, it may uncover a novel etiopathogenetic mechanism of sporadic AD.


2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 669-669
Author(s):  
Jacques P Tremblay ◽  
Antoine Guyon ◽  
Joël Rousseau ◽  
Guillaume Tremblay ◽  
Francis-Gabriel Begin ◽  
...  

Abstract There is currently no treatment for Alzheimer disease (AD). However, the Icelandic mutation in the APP gene (A673T) has been shown to confer a protection against the onset and development of AD (Jonsson et al. Nature 2012). This single nucleotide mutation in APP exon 16 reduces the cleavage of the APP protein by the beta-secretase by 40% thus preventing the development of AD even in persons more than 95 years old. Our research group has initially shown that the presence of the A673T mutation in an APP gene reduced the secretion of beta-amyloid peptides even if there is also a FAD mutation in the gene. This is the case for 14 different FAD mutations. We have used CRISPR/Cas9 base editing and PRIME editing technologies to insert the A673T mutation in the APP gene. We have compared several different cytidine base editor complexes to achieve the most effective and accurate genome modification possible in HEK293T cells and in SH-SY5Y neuroblastomas. The insertion of the A673T mutation in cells containing the London mutation reduced the secretion of beta-amyloid peptides. We are currently using lentiviral vectors to infect neurons from a mouse model and human neurons induced from fibroblasts of a patient with the London mutation. The insertion of the protective Icelandic mutation in the APP gene using these editing technologies opens a new potential therapeutic avenue not only for Familial Alzheimer’s diseases but also for sporadic Alzheimer’s disease.


2021 ◽  
Vol 17 (S5) ◽  
Author(s):  
Cleofé Peña‐Gomez ◽  
Muge Akinci ◽  
Gonzalo Sánchez‐Benavides ◽  
Mahnaz Shekari ◽  
Oriol Grau‐Rivera ◽  
...  

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